Ewing's U: Pete Anderson MD, PhD | Understanding Labs, Scans and Pathology

EPISODE TWO: On June 9, 2022, The Little Warrior Foundation + Dr. Pete discussed his perspective on how to interpret labs, scans and pathology.

NOTE: THE FOLLOWING IS THE OUTPUT OF TRANSCRIBING FROM AN AUDIO RECORDING. ALTHOUGH THE TRANSCRIPTION IS LARGELY ACCURATE, IN SOME CASES IT IS INCOMPLETE OR INACCURATE DUE TO INAUDIBLE PASSAGES OR TRANSCRIPTION ERRORS. IT IS POSTED AS AN AID TO UNDERSTANDING THE WEBINAR, BUT SHOULD NOT BE TREATED AS AN AUTHORITATIVE RECORD.

Maggie Spada: [00:00:02] Hello. Good afternoon, everybody. Welcome to our second episode of Ewing's U. I'm Maggie Spada, one of the co-founders of the Little Warrior Foundation and mom to 11 year old warrior Lucy. Today, we are going to be hearing from Dr. Pete Anderson as he breaks down many of the fundamentals, including labs, scans and pathology. Many of you know, Dr. Anderson, across the sarcoma community at large, he is revered as an expert, dedicated physician, outside the box thinker, and a catalyst for change. We are proud to say that Dr. Anderson is a member of the Little Little Warrior Medical Advisory Board, and he is also a grant recipient for his team's work with Ewing Sarcoma. But long before crossing paths with us at the Little Warrior Foundation, he has had a career that spans decades. Dr. Pete is currently a professor practicing pediatric hematology oncology at the Cleveland Clinic. He also practiced at the University of Texas, MD Anderson Cancer Cancer Center, where he was the section chief of non neural solid tumors, and at Mayo Clinic, where he launched the pediatric bone marrow transplant program. Dr. Anderson completes hundreds of virtual visits for sarcoma patients globally each year, and we are so honored to have him as our guest today. Before we turn it over to Dr. Pete, we have a few housekeeping items. First Ewing's you, Ewing's you production is an excuse me, a podcast and production of the Little Warrior Foundation. We are a National Childhood Cancer Foundation with a laser focus on finding a complete and permanent cure for Ewing Sarcoma. We were founded in April of 2020 and have granted out more than $1,000,000 to high potential therapies for increasing survivorship and decreasing toxicity for Ewing Sarcoma patients. We very much so rely on the support of the communities that support the patients on these calls. In order to make that possible - so we wanted to thank all of you and the many of you who have supported you on your journeys and donated so that we can bulldoze to a solution and continue this vital work. Piero I'll hand it over to you if you had another housekeeping item.

Piero Spada: [00:02:32] Yeah, thanks, Maggie. For those of you that don't know me, I'm Piero Spada, co-founder of the Little Warrior Foundation, also warrior dad to Lucy. And once again, I'm going to be your moderator for today. So grateful to have Dr. Pete with us as well as all of you. So a couple of housekeeping items. Number one, the format of today's webinar will be roughly 30 to 40 minutes of presentation by Dr. Pete, leaving us 15 to 20 minutes of a Q&A session. For your questions, we just kindly ask that you use the Q&A box in a lower right hand corner. Just simply type those in there, and that will help us get those through those questions. And then lastly, we cannot discuss any personal questions or case specific questions in this webinar. So just please keep that in mind when submitting your questions. And so before we hand it off to Dr. Pete, I'm going to pass it along to Emily. Thanks.

Emily McFadden: [00:03:23] Hi everyone. Thanks for joining. My name is Emily McFadden and I am one of the other co-founders of the Little Warrior Foundation. This session is going to be recorded and transcribed. It will be available on YouTube. Everything will be posted through our blog and everyone who has signed up to attend this webinar today will be receiving a follow up email. One important caveat with the audio transcription. We know that it's oftentimes a lot easier than listening to webinars. And however, particularly in the medical space, the audio transcription can be imperfect. So please keep that in mind and as you read through that. So without further ado, we'll kick it over to Dr. Pete to share his wisdom with all of us.

Dr. Pete: [00:04:22] Okay. Thank you very much. Let me pull up my slides here. And I assume you can see that. Fine. So what we'll be talking about is understanding labs, path reports and scans. I don't have any relevant disclosures except being from the north. I like winter as much as summer. And what will be trying to do is evaluating how you sort out all this information that we get now. And it's difficult not just for patients and families, but all the caregivers, the doctors, the nurses, the peers. We have a medical record. That helps organize it and MyChart helps families be very up to date. The problem is it's kind of like having a file cabinet with no dividers. So what I'd like to do is provide a framework of how you evaluate the mountain of information, anticipate what's next, so you have fewer bad surprises and you can ask questions. So first of all, with labs. When we get labs, there's all these different colored tubes. The way I like to think of it as the tried and true one is the CBC, which is a purple top. Now chemistries, which help us know a lot of other things about a person's health, may be in a green top, which is nice so it doesn't clot or a red top, so it does clot and then they run the test on the serum. I'll also talk about some labs that are index of inflammation like the C-reactive protein.

Dr. Pete: [00:06:21] And not to confuse you, but there's a lactate dehydrogenase enzyme that's a tumor marker, not to be confused with lactate, which is a product of metabolism. So first of all, the CBC is something that everybody sees a lot when you're on chemotherapy, even though it's called the complete blood count, it's actually incomplete unless you ask for a differential. The kinds of white cells and modern centers will often turn this around pretty quickly. In our clinic, less than an hour is not uncommon at all, and it's used to make decisions about infection risk, whether or not to get chemotherapy as your bone marrow recovered enough and see if you need transfusions. So on the CBC, one of the parameters that's reported is the hemoglobin. And if it's greater than ten, that's great. You don't get extra points for 11, 12, 13 or 14. You'll probably feel about the same 8 to 9.9. You might have a little bit of fatigue, but once you're under eight and certainly under seven, it's not uncommon to have a lot of fatigue. It's important to follow the trends. I call this connecting the dots. Is hemoglobin getting better or worse or staying the same? Another thing about red cells that will be reported on the CBC is their size if they're real big. Often they're young red cells we call reticular sites, and you're making good amount of blood.

Dr. Pete: [00:08:02] If they're real small, it might mean iron deficiency. And so the red cell count is on the CBC, but most of the doctors don't use this at all. And sometimes they'll report out the reticular sites. So when you look under the microscope, this is what blood looks like. We've got all these desks, which are red cells. They're about seven or eight microns in length, but they're a disc. So they're they're not as thick. The big cells are neutrophils and they're like 12 to 15 microns. And these little dots are platelets. They're about one. Some white cells called lymphocytes are small spheres, and they're 6 to 9. But if they're activated, they can be bigger. So when we look at the white cells we call neutrophils or polymorphic nuclear leukocytes, these are big white cells and they have many lobes of their nucleus. They're the kinds of white cells that help us fight bacteria and keep them where they're supposed to be. So if you have very few neutrophils, you can get bacteria from the mouth, intestines, rectum into the bloodstream and get really sick, which we call sepsis. So they talk about absolute neutrophil counts the percent PMNs times the total white count. Anything above 1000 will keep you out of trouble. 500 to 999 is low, but probably will also keep you out of trouble. But if it's less than 1.5, it might not be enough to keep you from having a fever and needing antibiotics.

Dr. Pete: [00:09:52] So we follow this absolute neutrophil trend. If it's going up and the ANC is greater than 750, for Ewing's, this gives you the go-no-go for chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifos, etoposide. It's not like you're at 750, you would be in horrible shape, that's probably fine, but we use this as a guideline. Not usually after chemo, the ANC will fall and then rise. You don't want to start chemo when you're still falling. Sometimes it can make the rise of the neutrophils higher and more quick. If you use drugs which stimulate the bone marrow to make more neutrophils such as granulocyte colony stimulating factor or the long acting G-CSF. Other white cells on the differential are lymphocytes and these help us fight viruses, including COVID, influenza, cytomegalovirus, even parasites that can cause a pneumonia. This is why many patients are on Bactrim when they have low lymphocytes. It's to prevent this pneumocystis pneumonia. But also, although we don't look at them as commonly lymphocytes, you can think of as the small good guys that help fight cancer and in sarcoma, that's been shown by a number of groups. We were the first to report and it just seemed kind of too good to be true. 14 days after your very first cycle of chemo, you had resilient lymphocytes that recovered fast. You did better. So the Dana-Farber group checked and it was even better results with their data set. So what you want to do is have good lymphocyte recovery and that facilitates better survival. If you have bad lymphocyte recovery and inflammation, it's kind of double trouble. So reducing toxicity during therapy is important, probably through the effect on lymphocytes.

Dr. Pete: [00:12:11] What do platelets do? They help our blood to clot. But they're pretty good at it until you get really, really low platelets, like less than 10,000. Most of the time this is associated with mucosal bleeding like nosebleeds. So it follows a trend. Sometimes I'll say. At this rate, you'll be in negative numbers, which is, of course, impossible, and you need a transfusion. But if they just stay stable at 15 or 20,000, you might not need a transfusion at all. Also, new platelets work better than old transfused platelets, and we can look for new platelets with another blood test called immature platelet fraction. How about chemistry? We don't get these every time we draw blood. Probably once chemotherapy cycle and the BUN/Creatinine tells us about kidney function. If they're low, good kidney function - high needs the kidneys less able to clear waste. Liver function, we look at bilirubin, AST and ALT enzymes which come from the liver. The liver's resilient, so you can see some changes here, but it will recover pretty quickly. Albumin on the chemistry tells us about liver able to make proteins like albumin so it's a nutrition index and then the lactate dehydrogenase is another enzyme in the blood that we can detect that's related to how much Ewing sarcoma you have.

Dr. Pete: [00:13:50] If we're worried about fever and neutropenia, we'll get a lactate. That's a great top too, that's a byproduct to glucose. And if lactate is high, it's associated with sepsis. If it's normal, usually it's just fever and neutropenia. And before Ifosfamide we'll check phosphorous. And this is because the phosphorus will get low and become normal before the next cycle. If it's always low, then you have cumulative kidney toxicity. Another blood test that we sometimes use the C-reactive protein, and this tells us how much inflammation you have. So we'll follow pneumonias this way, we'll follow infections. A normal C-reactive protein can be reassuring, and a trend where it's decreasing can be reassuring.

Dr. Pete: [00:14:45] So how about pathology reports? This is one of the more confusing things that we deal with with childhood cancers, but especially with when we look under the microscope, we see small round blue cells, but they can stain them with a special stain for CD-99. It's not 100% sure that it's Ewing's, but it's suggestive. And then we make the molecular diagnosis looking for the fusion gene of the Ewing Sarcoma FLI1 gene or Ewing Sarcoma ERG gene. When we talk about margins after surgery, that's how close the tumor is to the ink cut specimen. Anything greater than a millimeter is okay. If it's right up to the margin or cut through it, then you need to know that and plan ahead for it. And percent necrosis is how much of the tumor is dead. Often this will be associated with chemotherapy effect.

Dr. Pete: [00:15:52] So when we look under the microscope, this is what you and it looks like - just lots and lots of the same small round blue cells. If we stain for CD-99, you can see the gold here is the CD-99 expression. It's a reliable marker, but it's it's not 100%. Well, we look at percent necrosis. The reason we look at it is if it's 100%, patients do better. This is cumulative survival. And the more recent paper that came from the U.K. If it's medium, it's Okay. And if it's 0 to 50%, you can see half the patients are alive at five years that were in the good group. But it doesn't mean even good responders can relapse. So this is an Italian paper trying to figure out who were the good responders who still relapse. Pretty complicated for even the doctors to figure out. The bottom line is, you have to be ready at the end of therapy with the plan to follow.

Dr. Pete: [00:17:05] We look at molecular reports, they've come a very long way in the past five years. We went from saying the Ewing's gene is broken using fluorescence in situ hybridization or fish probe to say it's broken, to now we'll get reports that describe the gene fusion event, the Ewing's gene and its fusion partner. And now we can get the gene sequence and I'll show you some examples of this. So this is an example of a Tempus report. They'll say EWS-FLI1 once rearranged, and your doctor can help you with interpretation of all the information on these reports, sometimes more than you would think is available, like other mutations, which genes are expressed. This report sometimes lists clinical trials, but your doctor can help you with that. Also, they'll look at other kinds of - an example from Foundation One, looking at other genes which are either lost or gained or mutated. The lung metastases are the best for molecular analysis because unlike bone, you don't have the deep calcified specimen and de-calcification will destroy the DNA and RNA. So your doctors have to be, especially surgeons, knowledgeable that you want the molecular tests done and then they'll do it right. This gives an example of our Cleveland Clinic Foundation Sarcoma next generation sequencing panel. It'll tell us it's done on a paraffin block, which is the fusion gene detected in this case EWS-FLI1 and then it'll tell us the exact part of the gene that's broken and fused to the other gene. This gene, it's only in cancer cells, it's not in any normal cells.

Dr. Pete: [00:19:16] Then I'll take that report. I'll email our informatics specialist and he'll look at the breakpoint analysis exactly where the gene is broken, down to the DNA base. And then he'll email me back a whole bunch of letters, which it's hard to make any sense of this, there's so many. But it comes down to if he does the end frame analysis, what are these coding for? If this was translated into mRNA and then amino acids for proteins, you would get a peptide. So the blue here is the normal sequence of peptides in the EWS normal gene, but then it's broken here and fused to FLI1 the red is the peptides for the FLI1 gene. So by just getting a portion of this information at a glance, you can see that these what they're like and many patients will have the exon 7-7 or 7-6, about 75%. So I get this information. It's possible we may have future vaccines in the future. They're not available now, but you have the information, then you'll know. And this also shows you're 100% certain of which molecular events is driving the tumor for a particular patient.

Dr. Pete: [00:20:43] So the next is radiology reports. Believe it or not, I don't call myself old, I call myself experienced. And they're still confusing because they're wordy. Sometimes the radiologists will use terms that sound scary, but really what you're trying to do is figure out what story are they trying to tell with words? So what I end up doing is looking at images, the pictures tell the story. What the radiologist is doing is trying to describe that story in words. CTs have hundreds of images, MRIs, sometimes thousands. So you end up with a very wordy legend for a very long series of pictures. And there's differences in the quality of reports. Sometimes the terms make it sound much worse, like regression or new or "ground glass" or larger when they're very, very similar to the last scan. So first thing I tell myself is to slow down and look at the images and compare on your own. So the way I do that is the best case is you know where to look. The report might tell you which series, which image, which part of the lung to look at. New findings should be compared to old scans. Sometimes I'll even look at the size of a particular lesion, whether it's in a soft tissue, bone or lung anterior posterior, so that's front to back. Transverse side to side and cranial caudal, up and down. And if you remember, geometry, 4/3 Pir^3 will give you the volume of an ellipsoid. So small changes in these dimensions are reflected in volume. But I think of it as seeing, is believing. And I'll often make PowerPoints with legends so I can communicate this to the patient and their caregivers, but also illustrate my notes so I can communicate with other doctors.

Dr. Pete: [00:23:08] One way to think of it as this is probably my favorite Dr. Seuss book, I Had Troubles of More Than One Kind, some from ahead and Some from behind. So what you're trying to do is look at the trends. So how do I do that and communicate? Sometimes I need extra time to look at labs, images, path reports. And then I can do a virtual visit for information and education, whether they live in northern Ohio or not. This helps all of us avoid battle fatigue and snap judgments. Also, virtual visits are less stressful environment, particularly patients in California or mountain time. When I do the virtual visits on Eastern Time, you can see they've just gotten up, and they're having coffee. It's a much easier, less stressful time. And this facilitates therapeutic alliances. So if you need help in interpreting labs, health reports or scans, ask your doctor about virtual visits or me. And they're a good way to learn. So there's many opportunities to use labs, path reports for what I call forward observation. This will help you to have fewer side effects and an adaptive approach, particularly as you follow trends. And as you learn more, your questions will get better and better, just like you're doing now. So like to open it up for questions. I'll do the sharing. And. I guess it goes back to.

Piero Spada: [00:24:57] Yeah us.

Dr. Pete: [00:24:57] And Piero.

Dr. Pete: [00:24:59] Yeah. Well, thank you for that, Dr. Pete. Chock-full of information. I'm sure glad that that was recorded because I'm sure I will even be going back and digging in to that one lot's of information. I think the first questions we're going to ask actually comes from email. So this is our second episode and we actually had an email prior to this webinar from a Warrior Dad. And it's two pronged, both from the clinician standpoint and the patient side, and it pertains to your virtual visits. And really this person wants to know, is there a difference between a second opinion and a consult when doing your virtual visits? And secondarily, how do you work with a local team from afar? Like how involved are you in the in the care with these virtual visits?

Dr. Pete: [00:25:45] Oh, those are great questions. Second, opinions and consults are commonly thought of as the same. A second opinion is more formal. It might be in writing. We do virtual second opinions here for foreign patients. I guess the way I see it is and I've done this pre-pandemic, it's like two years before the pandemic. I see the virtual visits as providing education and information. They're not to direct care. It would be impossible for me to supervise somebody's chemotherapy or blood counts or side effects 1000 miles away, because if they had issues, they're going to have to go see their local oncologist. Rather it's to help them develop what I call therapeutic alliances, so they use all the people on their team. And sometimes things are counterintuitive. For example, if you have metastases, it's helpful to talk to palliative care and the social worker put advance directives in place so the whole team is not afraid of treating the patient. They don't just keep saying over and over again, this is bad, but rather everybody can move on to what can be done in this situation. So it goes back to my PhD is in biochemical genetics. So I see my role as like an enzyme to lower the activation energy, so good things can happen. It's not to interfere in care at all, but rather help patients and families to be more knowledgeable about what resources they have. And if they don't have resources at the center, they're (going) have to find one that's good for them. Of course, I love Cleveland, but there are other places that have excellent radiation oncology and surgeons and oncology pharmacists, so it's kind of learned to use all those resources is the way I see virtual visits.

Piero Spada: [00:28:16] Thanks for that. I love the enzyme analogy that brought me back to intro biochemistry there. So on the flip side of that, from the patient side, whenever the patients or the patient families are interested in getting a second opinion, is there something are there tips that you can provide that help facilitate the type of information you or another doctor would need to see in order to take a look at a case?

Dr. Pete: [00:28:40] Yeah, there are. Time is the hardest thing for doctors to give up. There. I don't know any that are not overcommitted. And so, what can you do to make things friendly and efficient for them? So sometimes that means things like. If you've never seen this doctor before, having a short half page summary of the history so you know, at a glance or instead of a big, long narrative. Or an outline of important topics. If scans need to be reviewed, giving them enough time to review them, it causes me anxiety to look at a chest CT on the same day that I see somebody. But sometimes it means being able to adapt if you have a new finding. So we'll get more information about this and then talk. So, put yourself, especially for medical oncologists who are even busier than peds oncologists. They see more patients in a particular day. What you're trying to do is to help them. Not only get through their clinic, but do in a way that they can be thoughtful and get things done efficiently. So sometimes it means being the first or the last patient of the day.

Piero Spada: [00:30:27] Thanks, Emily. Do you want. Do you have a question cued up or do you want me to keep going?

Emily McFadden: [00:30:35] You did. This is my first time on Zoom. I'm kidding. We have a question here. Why is tumor response based on necrosis but not shrinkage?

Dr. Pete: [00:30:49] Two reasons one traditional. That's the papers that were published by Piero Picci and his group in Italy a long time ago. That seemed to be, more predictive. The other is our scans weren't that good 20 years ago. We didn't have three dimensions in axial coronal and sagittal views. I've seen them as standard on scans only, I'd say, in the last 5 to 10 years. So we couldn't look at tumor volume then. Also, around 2007-2008, clinical trials started using just one dimension. We call it the RESIST criteria, response, evaluation, imaging. And for tumors in the lungs, we just look at the longest diameter. So it's only recently we found all three diameters and it takes somebody motivated to calculate a volume. I'll do it sometimes when people go "it didn't shrink very much", and then they'll calculate the volume and actually the volume decrease 70, 80%. So it's just the mathematics of how that is. But it helps you understand you're going in the right direction. Other reasons we don't use tumor volumes is it requires looking at the, the metastasis or the tumor exactly the same way each time. So it's easier to try to do that in one dimension than three.

Piero Spada: [00:32:47] All right. Thanks for that. So the next question is kind of surrounding NGS, the ever expanding role that that's playing on diagnosis. And I guess from the patient perspective, especially upon first diagnoses, parents don't know what, they don't know. Right. And I guess the question surrounds how much tumor biopsy sample is required to do the preferred minimum of NGS and what type of sequencing is recommended right now? In 2022. 

Dr. Pete: [00:33:19] A moving target because we're getting better at it. What's required is a small sample that's not de-calcified. So if they have, let's say, interventional radiology to do biopsies, they should get a minimum three, but probably 4 to 6 cores and set one of them aside after they get the diagnosis of what they think it is, then they confirm it with the molecular sample. Not every place will run an entire NGS that's devoted to sarcoma like Cleveland Clinic does. Some will send them out to Tempus or Boston Gene or Foundation One or Caris. Each center probably has its pathway they've developed with the pathologists. And what's hard is you don't know the diagnosis when you're doing the biopsy. All you can say is we suspect it's a childhood sarcoma. So usually what you try to do is have enough sample so you can do extra tests. Now, at the time of relapse or removal of lung metastases, that's different than you already know the diagnosis. And you can say after we've established that this is not an infection and it's recurrent Ewings, for example, we would like the sample sent for molecular testing. Then you can talk to your doctor and figure out who they usually use at your center. If they don't, then send it to a sarcoma center that they're familiar with. To put things in perspective, our pathologists probably see six times more cases than the medical oncologists and peds oncologists here because they're really good at rare sarcoma stuff. And it's been funny once we got the NGSs like there's one case of a I remember, we thought it was a Desmoplastic Small Round Cell Tumor. So it should have been, EWS-WT1 fusion. And it turned out it was so rare. I had never seen it before us. It was EWS-ZNF44. But I was able to talk to the pathologists say this is how to present it. This is kind of, Response she's had to therapy. This is what we should do so the information can be real helpful or in the future, I would hope we have tests looking at circulating cell free DNA. And then knowing what you have up front, it helps them to know what to look for and how to look for it, because they can span that break point that's broken.

Piero Spada: [00:36:41] I guess on that note, as there, as a leading expert, is there a bare minimum that you would want to see as a medical oncologist from that report? Or is it truly case specific?

Dr. Pete: [00:36:56] The minimum is is which genes are broken and fused together. To get a higher mark, if they can tell you which exons are broken, and the highest marks are the overachievers who actually look at the-- and they can do this, they just don't routinely do it because it doesn't affect our diagnosis. It just affects our knowledge of Ewing sarcoma in general. And hopefully we'll have this information for future clinical trials would be the exact DNA sequence and in-frame analysis.

Piero Spada: [00:37:35] Thank you.

Emily McFadden: [00:37:38] Great. This next question actually touches on a topic you just brought up. Circulating tumor DNA and blood tests. What role does that play today, if any, and where do you see that technology moving?

Dr. Pete: [00:38:01] It's interesting, the oncologists have a yearly meeting in Chicago - American Society of Clinical Oncology and. They had quite a few sessions for quite a few different tumors devoted to circulating tumor DNA. So you know what to look for from analysis of the original tumor. The ability to look for it's getting better and better. So it's becoming mainstream for some common cancers like lung cancer, colon cancer, pancreatic cancer, they can detect point mutations. For sarcomas. There's not a big market. So we've been a little slow to get it mainstream. But I think with time, especially if it affects therapy in the future, you know, to treat longer or shorter, to treat more intensively or less intensively like we do for leukemia nowadays, it will make the difference. So my advice is stay tuned. Ask your doctor. There are some consortiums that are looking at this now. Matteo Trucco here has a protocol open for this for a variety of sarcomas. And we'll probably just get better and better at it with time.

Piero Spada: [00:39:44] Thanks for that, Dr. Pete. So we have a question surrounding targeted therapy. And I'm assuming this is in the relapse scenario and the role that targeted therapy plays. And they listed several gene markers as such as TP53, CDKN2A, is that do we have anything in our arsenal to go after said biomarkers and where are we at with targeted therapy for Ewing's.

Dr. Pete: [00:40:11] Every time we thought we had a biomarker. It hasn't worked so far for Ewings. It's hard to go from, cell lines, to animals like mice with a Ewings tumor to then humans. Some trials will require knowledge of what the target is. Give you an example, there is a IGF1R antibody that works maybe 25% of the time on its own to get a response in Ewing's. But the responses were transient and the trial I did was an international trial when I was at M.D. Anderson, only five of 78 patients were treated for five years. So now they have that antibody, but with an alpha-emitting tag on it. So for that trial, in order to go through all the work of getting an antibody with a radiopharmaceutical on it, you want to make sure the tumor has good imaging. So that's a good example of a targeted therapy. That it would use imaging to actually tell you the target you can look under the microscope, but the imaging gives you the assurance that it will do what it's supposed to do. So each trial is different. How they do that?

Piero Spada: [00:41:59] Thanks.

Emily McFadden: [00:42:01] Okay. My question just came in about maintenance therapies, and is there a discussion about the prevention, prevention treatment or for recurrence and relapse?

Dr. Pete: [00:42:19] That's been a hot topic for years. The doctors at Sloan-Kettering have a clinical trial for high risk patients where they get additional therapy as a maintenance. As far as I know, the results aren't out yet, but you would hope there was improvement. There's a trial at Nationwide right now, and they're trying to get a consortium of centers to use Cabozantinib as a maintenance, even if you don't have measurable disease. Other maintenance's we've talked about this at the National Tumor Board, Atlanta has a trial using metronomic therapy with oral cyclophosphamide, etoposide a mTOR inhibitor. We don't know how well they work, but if rhabdomyosarcoma is any indication where oral cyclophosphamide, vinorelbine improves survival. We would hope that we'll find something in Ewings that does for the high risk patients. I like to think of it as you wanted to do a stellar job up front. So if you have lung metastases, get whole lung radiation, have bone metastases, get SBRT. That's probably as important as a maintenance. Treating all known sites of disease.

Piero Spada: [00:44:07] So aggressive local control, correct?

Dr. Pete: [00:44:10] Yeah.

Piero Spada: [00:44:12] Thanks for that. So we had a question, just a General Ewing's question. How can patients stay up to date on like cutting edge breakthroughs in the Ewing's realm? And so for both, from the patient standpoint and I guess, where do you look for information as well as a doctor?

Dr. Pete: [00:44:29] Well, of course, the Little Warriors Foundation.

Piero Spada: [00:44:32] Well said.

Dr. Pete: [00:44:33] But it's funny, the virtual visits. I learn as much from the patients as they learn from me sometimes. Also, each center has a different flavor. You can just follow recipes, but some centers, what we want to do is learn from each other. And that's what we do at Cleveland Clinic with both journal clubs as well as tumor boards. If you learn something, then you share them. Otherwise it's just never known to other people. So try to have an attitude of curiosity, but openness to new ideas. I think many of the online groups can be quite helpful, but also they can be somewhat overwhelming sometimes because everybody has different circumstances, some better, some worse. Another way to look at clinical trials is the clinicaltrials.gov information. So when you search you'll get that, make a PDF of it, but that's just a starting place. You may want to get the eligibility and exclusion criteria. You may want to do a virtual visit to see if it's a reasonable thing to do instead of buy three plane tickets and then get a disappointment, either the trials not open or not right for what you have. But sometimes that means just having an unrushed visit. So sometimes the initial consult will be gathering information and then you'll have what I call an exit conference where you decide what's what's best. And that's how you can have the time to process the information and then learn about things and ask intelligent questions. Always listen to mothers, too. They know their children so well, you know, and they put extra effort into learning things. So if you can learn from others, you can't go wrong.

Piero Spada: [00:47:07] Emily, do you have another question? You want to keep going?

Emily McFadden: [00:47:11] Yeah. A question just came in. This is my my type of question. So what is a general type or targeted trial you might like, you would like to pursue if you could eliminate obstacles like your time and funding as a barrier?

Dr. Pete: [00:47:33] What I -- it's funny. My experience is kind of been that the trials that people want to do are the ones that don't have a lot of toxicity. So it makes it fun as a doctor, but also as a caregiver and a patient instead of being something, you know, you dread, you know, it's like - Easy. So you want to design a trial that, is thoughtful in terms of having a good quality of life while you're on the therapy. In terms of reducing barriers, there's probably four ways to do it. One of them is provide lots of information up front, so if it's right for them, then they come for the trial. That might require virtual visits or a hand-out of information. Sometimes the consent forms are so long you can't understand them. But if there's diagrams about what the trial is about, that makes it easier. Also, the other barriers funding. Clinical research can be phenomenally expensive for drug companies. They have to pay their people. Sometimes they'll pay a contract research organization to make sure data is collected. And, within the center, you have to have yearly reviews by your own IRB. If it's an experimental drug, the FDA will have yearly reviews of the IND number. So you need to pay people good enough salaries to have the time to do a good job for all those regulatory issues. And that makes it expensive. Ideally you would have a very efficient team that's small enough so they can get things done and talk to each other and large enough to have experience. So there's a happy medium. Usually that's in a centre that's medium to large size that people have a special interest in a particular disease. So here, give you an example. It's Ewing's but one of our pathologists is an expert on a very rare sarcoma. We got a trial going in the SARC consortium, so. I think getting people where it's a passion, not an obligation, would lower a lot of barriers. That's hard to do because many of us are overcommitted.

Piero Spada: [00:50:45] Alright, great response. So I think we're going to finish with two last questions here, Dr. Pete. One will be very specific, and then one we like to just have that's very open ended, if that's alright with you.

Dr. Pete: [00:50:54] Sure.

Piero Spada: [00:50:55] So there's, this is actually a perfect perhaps segway for a future discussion, but it's what are your thoughts around a vaccine for Ewing's that are neoantigen based and they specifically list Neo7logix as one potential vaccine or others. Can they work?

Dr. Pete: [00:51:13] I think they can work if they're cancer specific and not just normal antigen that's expressed higher in a cancer cell. That said, how do you get longer lasting immunity? Because you don't want a vaccine that just works for a little bit of time and then you get a relapse. So you have to I call it reverse engineer the vaccine. You need an immunologic adjuvant with whatever you're immunizing to. Nature's adjuvants are cytokines, but I think there's ways for companies to actually incorporate that in vaccines. So I would hope future vaccines do something like that instead of just combine with a checkpoint inhibitor or something like that, particularly for Ewing's. In terms of the particular trials, what you have to do is look at what you're trying to develop immunity to and what are the yardsticks so, you know, whether you do or not. Sometimes there'll be blood tests, but another one to think about would be a skin test, just like a TB skin test. When your T-cells respond to TB, you get this little, little bump. And if you could have visual proof that you're responding to your tumor antigen, that would be very reassuring to both the doctor and the patient. So I'd like to see that develop as part of any vaccine trial.

Piero Spada: [00:52:58] Fantastic. One can only hope that we would have that for Ewing someday and hopefully soon too. The last question I have for you is open ended, so feel free to answer this any way you feel. But we just simply like to ask what gives you hope? Or gives you the most hope.

Dr. Pete: [00:53:17] To see, how far we've gone, in a relatively short time for not only molecular characterization, but how well people can work together during the pandemic. That's the silver lining. Like this Zoom call. 

Piero Spada: [00:53:39] Right.

Dr. Pete: [00:53:42] Four years ago, we were using a clunky software called American Well. Sometimes it would drop, it just going, okay, now I have to call him on the phone or do face time. Now people reliably know how to use Zoom and the world's really become a much smaller place. So it gives me hope that you don't get smart talking to yourself. But we'll get more people interested in rare diseases who can work with each other in ways we never imagined.

Piero Spada: [00:54:21] Well said. And thanks for this discussion and presentation, Dr. Pete. I'm going to hand it off to Maggie to close it out for us. Thoroughly enjoyed this, though. Thank you.

Dr. Pete: [00:54:28] Thank you.

Maggie Spada: [00:54:30] Now we could listen to you talk for hours. And I also have to say, because our moderators weren't sure how to convey this, but there's multiple just shout outs to you in the chat. Not questions, just like expressions of love and gratitude. So I wanted to share that with you. We talk a lot about at Little Warrior Foundation, about hope and combining hope with hustle and what can be done. But I just wanted to say that for so many of the people on this call, your thoughtful and cutting edge practice has been that hope for so many families, ours included. And you practice hope by your consistently calm demeanor. I feel calmer now than I did an hour ago, I'll tell you that right now. You do it by responding to late night frantic emails from parents at 4 a.m. You do it by listening to your patients. You treat the whole patient and you genuinely care about what is going on in their lives outside of the four exam walls or after the Zoom meeting ends. And so I know there are many, many people who wish they could unmute and express their gratitude to you right now. So I will do that on their behalf and say thank you for touching our lives and please accept our sincere gratitude for being available just to share the small bit of your knowledge today.

Dr. Pete: [00:55:52] Well, that's a pleasure. Thank you.

Maggie Spada: [00:55:53] You're welcome. With that, summer is a busy season here at Little Warrior Foundation. Our team is going to be hitting the ground running with volunteers and team members working hard to fundraise for future research endeavors. So we are going to take July off for Ewing's U, but we will be back in August and then scheduled at least monthly going through the rest of the calendar year. Feel free to visit our website. You can navigate to the Ewing's U section to sign up so that you can get alerted of future events and be notified as those come up. Finally, we have a phrase here, a Little Warrior that we feel embodies our fight in honor of and in memory of too many patients. It is how we sign off on our emails and our communications internally and with physicians, and it is how we will sign off today on our Ewing's U episode. So one, two, three. Swords Up. Take care.